Prospective Feasibility Trial of Pharmacokinetic Directed Melphalan for Lymphoma Patients Undergoing Autologous Hematopoietic Cell Transplantation

Background

BEAM [carmustine (BCNU), etoposide (E), cytarabine (Ara-C) and melphalan (M)] followed by autologous hematopoietic cell transplantation (autoHCT) is an established treatment for patients with relapsed lymphoma with curative potential, and carries a significant burden of organ toxicity, limiting its use in older or comorbid patients. Pharmacokinetic (PK) targeted dosing of melphalan is an attractive strategy to achieve optimal exposure to limit toxicity without compromising efficacy.

We previously developed a population PK model for melphalan which predicts drug exposure with a high degree of accuracy. We reported melphalan exposure in patients undergoing BEAM autoHCT measured by direct AUC calculation and compared this to our population PK model. We found there was a wide (>5 fold) variability in AUC with traditional dosing. The median AUC in this group was 8.9mg*h/L (range 4.1-23mg*h/L). Based on a clear separation that was demonstrated in cumulative incidence of toxicity between patients who had AUCs below or above the median, we hypothesized that a melphalan AUC of 8.5 +/- 1.5 mg*h/L may be an optimal target to balance the efficacy of melphalan with its toxicity.

Methods

In this open label, single institutional trial we evaluated the feasibility of using population PK model-directed melphalan dosing to achieve a target melphalan AUC of 8.5 +/-1.5 mg*h/L in patients undergoing BEAM autoHCT (NCT05540340). All other components of the BEAM regimen were delivered as standard of care. Using the benchmark set in other targeted dosing protocols, success for this study was defined if at least 80% of patients achieved the target AUC range. Secondary endpoints included incidence of toxicities, engraftment, progression-free survival (PFS), overall survival (OS) and hospital length of stay (LOS).

Results

Between January 2023 and February 2024, 16 patients were treated on study. Median follow up was 11.3 months (IQR 4.8-13.2 months). Patients were treated for diffuse large B cell lymphoma (DLBCL) (n=7), follicular lymphoma (FL) grade 3B (n=1), T-cell lymphoma (TCL) (n=7), and composite FL grade 3B and TCL (n=1). Median HCT comorbidity index (HCT-CI) was 4 (range 1-8). Median age was 64 (range 45-76) and 25% of patients were non-white.

The median dose of melphalan received was 105.8 mg/m2 (range 87-132 mg/m2). The median absolute melphalan dose received was 208.5 mg (range 140-270 mg). Median melphalan AUC achieved was 9.2 mg*h/L (range 6.2-13.3). Target AUC of 8.5 +/- 1.5 mg*h/L was achieved in 8 (50%) of patients. 87.5% of patients achieved an AUC exposure equal or greater than the target level, with only 2 patients (12.5%) achieving a lower than target AUC. The administered dose of melphalan was less than standard 140mg/m2 dose in all cases.

Median OS and PFS was not reached. At 12-months OS was 80% and PFS was 74%. There was a significant improvement in OS in patients who achieved an AUC within or below the target range (AUC≤10) compared to those above the target (AUC>10) (p=0.035). There was no significant difference in PFS between the groups.

One patient (AUC 11.9) developed grade ≥3 mucositis. Incidence of other grade ≥3 non-hematological toxicities was 50% in patients with AUC≤10, and 83% with AUC>10. Median hospital LOS was 19 in patients with AUC≤10, and 21 in patients AUC>10. Median time to neutrophil and platelet engraftment was 9 days and 19 days respectively. There was no significant difference in time to engraftment between groups.

Two patients died within 30 days of autoHCT. Both patients were highly co-morbid with an HCT-CI of 6. Both achieved an AUC greater than the target (12.4 and 11.9 mg*h/L, respectively), despite receiving the PK-directed dosing which was less than the standard 140mg/m2 dose of melphalan that they otherwise would have received in a usual BEAM regimen (99.5 and 123 mg/m2, respectively).

Conclusions

Our population PK model for melphalan dosing in patients receiving BEAM led to greatly improved variability in AUC exposure. The AUC exposures were equal or greater to the target in most cases. While the administered dose of melphalan was lower than traditional doses (less than standard 140mg/m2 in all cases), PFS and OS remained highly favorable. This approach shows great promise in improving tolerability and deliverability of BEAM. In order to further refine the rate of achieving target exposure with population PK model dosing, a second cohort using a split dose melphalan is underway.

Lin:Sanofi: Consultancy. Perales:Nektar: Research Funding; Novartis: Research Funding; Biotec: Research Funding; Miltenyi: Research Funding; Kite/Gilead: Research Funding; Incyte: Research Funding; Allogene: Research Funding; OrcaBio: Current equity holder in private company; Omeros: Current Employment, Current equity holder in publicly-traded company; NexImmune: Current Employment, Current equity holder in publicly-traded company. Scordo:MJH Life Sciences (Cancer Network): Honoraria; Miltenyi Biotec: Consultancy; Medscape: Honoraria; Amgen: Research Funding; IDEOlogy: Honoraria; Sanofi: Research Funding; Angiocrine Biosciences, Inc.: Research Funding; Kite - A Gilead Company: Consultancy; Omeros Corporation: Consultancy, Research Funding. Shah:Janssen, Amgen, Beyond Spring, BMS, GPCR, DSMB with ArcellX.: Research Funding.